Abstract

Most agents that either cause or cure cancer react with DNA to form products collectively referred to as adducts. Adducts are believed to act as the functional precursors to cancer and possibly other genetic diseases by causing mutations or even more complex genetic events. Adducts also can kill cells by interfering with normal replication and transcription; the killing property of DNA damaging agents has been exploited in the design of antitumor drugs. The objective of the research of this laboratory is to investigate the mechanisms of mutagenesis, genotoxicity and DNA repair of a series of adducts formed by DNA damaging agents of relevance to human health. The carcinogenic chemicals we investigate include mycotoxins, aromatic amines, short-chain alkylating agents, organic carbonyl compounds and vinyl halides. We also study inorganic complexes of, and related to, the antitumor drug cisdiamminedichloroplatinum (II). Finally, we are investigating the genetic after-effects of DNA damage by ionizing radiation and oxidation. To accomplish our goals, we use the tools of chemical synthesis and recombinant DNA technology to construct viral or plasmid vectors that contain, at specific genome locations, the known DNA adducts formed by the DNA damaging agents listed above. Site-specifically modified genomes are then introduced into bacterial or mammalian cells, where the single DNA lesion is acted upon in a presumably normal way by the cell's replication/repair systems. We next characterize the amount and type of mutations induced through misreplication or misrepair of the adducted genome. We also determine the relative genotoxic potentials of the individual adducts formed by the chemicals (or radiations) under study. With this information, we attempt to establish formal rules that relate the structure of the DNA lesion with its biological effects. Finally, since DNA repair proteins modulate the genotoxicity of many antitumor drugs, as well as many chemical and physical carcinogens, we attempt to elucidate the biochemical pathway(s) by which the DNA adducts are repaired in mammalian cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA052127-03
Application #
3479786
Study Section
Special Emphasis Panel (SRC (N2))
Project Start
1990-06-20
Project End
1997-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Massachusetts Institute of Technology
Department
Type
Other Domestic Higher Education
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139

  Publications

Zdraveski, Z Z; Mello, J A; Marinus, M G et al. (2000) Multiple pathways of recombination define cellular responses to cisplatin. Chem Biol 7:39-50
Trimmer, E E; Essigmann, J M (1999) Cisplatin. Essays Biochem 34:191-211
Avery, A M; Kaur, B; Taylor, J S et al. (1999) Substrate specificity of ultraviolet DNA endonuclease (UVDE/Uve1p) from Schizosaccharomyces pombe. Nucleic Acids Res 27:2256-64
Pourquier, P; Ueng, L M; Fertala, J et al. (1999) Induction of reversible complexes between eukaryotic DNA topoisomerase I and DNA-containing oxidative base damages. 7, 8-dihydro-8-oxoguanine and 5-hydroxycytosine. J Biol Chem 274:8516-23
Loeb, L A; Essigmann, J M; Kazazi, F et al. (1999) Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proc Natl Acad Sci U S A 96:1492-7
Kreutzer, D A; Essigmann, J M (1998) Oxidized, deaminated cytosines are a source of C --> T transitions in vivo. Proc Natl Acad Sci U S A 95:3578-82
Zhai, X; Beckmann, H; Jantzen, H M et al. (1998) Cisplatin-DNA adducts inhibit ribosomal RNA synthesis by hijacking the transcription factor human upstream binding factor. Biochemistry 37:16307-15
Trimmer, E E; Zamble, D B; Lippard, S J et al. (1998) Human testis-determining factor SRY binds to the major DNA adduct of cisplatin and a putative target sequence with comparable affinities. Biochemistry 37:352-62
Kobertz, W R; Wang, D; Wogan, G N et al. (1997) An intercalation inhibitor altering the target selectivity of DNA damaging agents: synthesis of site-specific aflatoxin B1 adducts in a p53 mutational hotspot. Proc Natl Acad Sci U S A 94:9579-84
Verghis, S B; Essigmann, J M; Kadlubar, F F et al. (1997) Specificity of mutagenesis by 4-aminobiphenyl: mutations at G residues in bacteriophage M13 DNA and G-->C transversions at a unique dG(8-ABP) lesion in single-stranded DNA. Carcinogenesis 18:2403-14

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